Immunotherapy, Inflammation and Colorectal Cancer

Abstract

Colorectal cancer (CRC) is the third most common cancer type, and third highest in mortality rates among cancer-related deaths in the United States. Originating from intestinal epithelial cells in the colon and rectum, that are impacted by numerous factors including genetics, environment and chronic, lingering inflammation, CRC can be a problematic malignancy to treat when detected at advanced stages. Chemotherapeutic agents serve as the historical first line of defense in the treatment of metastatic CRC. In recent years, however, combinational treatment with targeted therapies, such as vascular endothelial growth factor, or epidermal growth factor receptor inhibitors, has proven to be quite effective in patients with specific CRC subtypes. While scientific and clinical advances have uncovered promising new treatment options, the five-year survival rate for metastatic CRC is still low at about 14%. Current research into the efficacy of immunotherapy, particularly immune checkpoint inhibitor therapy (ICI) in mismatch repair deficient and microsatellite instability high (dMMR-MSI-H) CRC tumors have shown promising results, but its use in other CRC subtypes has been either unsuccessful, or not extensively explored. This Review will focus on the current status of immunotherapies, including ICI, vaccination and adoptive T cell therapy (ATC) in the treatment of CRC and its potential use, not only in dMMR-MSI-H CRC, but also in mismatch repair proficient and microsatellite instability low (pMMR-MSI-L).

Keywords: colorectal cancer; immunotherapy; inflammation; microsatellite instability.

Figure 1

Intrinsic and extrinsic factors contributing to the pathogenesis of colorectal cancer (CRC). CRC can develop from a multitude of both intrinsic and extrinsic factors. Extrinsic factors, including inflammation from hyperactivated immune cells, the release of proinflammatory cytokines, or gut dysbiosis, can lead to an inflammatory and possibly premalignant environment. Intrinsic factors include sporadic mutations, such as those leading to mutation-induced CRC (sporadic CRC). Similarly, precancerous mutations, or mutations induced by prior inflammation, can lead to colitis-associated cancer (CAC), a specific subset of CRC stemming from chronic inflammation caused by inflammatory bowel disease (IBD), specifically ulcerative colitis (UC) or Crohn’s disease (CD).

Figure 2

Immuno-landscape of dMMR-MSI-H and pMMR-MSI-L CRC. CRC can be classified into two subsets based on its MMR/MSI status. The DNA MMR system relies on key genes, such as MLH1, MSH2, MSH6, PMS2, or MSH3, that correct mismatched or wrongly inserted or deleted bases in the DNA. If this machinery fails due to defects in one or more of the repair genes, these errors are free to be integrated into the DNA permanently, forming microsatellites. Thus, dMMR-MSI-H tumors are those that have a defect in one of the major DNA repair genes (dMMR), resulting in high levels of microsatellites (MSI-H). On the other hand, pMMR-MSI-L tumors have a functional MMR system (pMMR), resulting in low or stable levels of microsatellites (MSI-L). The result of this damaged repair system in dMMR-MSI-H tumors is a higher mutational burden, which correlates with a higher expression of neoantigens on MHC-I molecules.

Figure 3

The future of CRC therapy: combinatorial agents. The current status of the use of inhibitor therapy (ICI) in the treatment of CRC has shown promising results, despite the lack of a complete response in dMMR-MSI-H tumors, and no response in pMMR-MSI-L. This obstacle has paved the way for insight and research into plausible combinatorial agents that can overcome this scientific impediment. (A) ICI in combination with AMG 510, a KRAS (G12C) inhibitor, or (B) therapeutic cancer vaccines, or (C) adoptive T cell therapy, or (D) TNF and TGFβ inhibitors may serve as the next candidates for combinatorial therapy with ICI.